A plant-derived morphinan as a novel lead compound active against malaria liver stages
A plant-derived morphinan as a novel lead compound active against malaria liver stages
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DOI：
10.1371/journal.pmed.0030513
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发表时间：
2006-12-01
期刊：
影响因子：
15.8
通讯作者：
Mazier, Dominique
中科院分区：
文献类型：
--
作者：
Carraz, Maeelle;Jossang, Akino;Mazier, Dominique
背景随着耐多药疟疾寄生虫的全球传播，迫切需要新的化疗药物。药物发现主要针对无性性血液阶段，自20世纪50年代使用伯氨喹以来，很少有药物能有效地对抗引起致病性血液感染的强制性肝脏阶段。利用基于寄生虫肝脏阶段的生物测定指导分离，我们从马达加斯加一种传统上用于治疗疟疾的植物中分离出一种新的吗啡inan生物碱——tazopsine。在体外（恶性疟原虫和约氏疟原虫）和体内（约氏疟原虫）测试了该化合物和容易获得的半合成衍生物对肝期发育的抑制活性。Tazopsine在培养的原代肝细胞中完全抑制约氏疟原虫（50%抑制浓度[IC50] 3.1 μ M，治疗指数[TI] 14）和恶性疟原虫（IC50] 4.2 μ M，治疗指数[TI] 7）肝寄生虫的发育，且在发育早期抑制最为明显。一种衍生物n -环戊基-tazopsine （NCP-tazopsine）具有相似的抑制活性，因其对约氏疟原虫和恶性疟原虫肝期的体外毒性较低（IC50分别为3.3 μ M， TI 46和42.4 μ M, TI 60）。口服NCP-tazopsine完全保护小鼠免受孢子虫的攻击。与母体分子不同，该衍生物对肝期疟原虫具有独特的活性。结论：一种容易获得的植物源化合物的半合成衍生物tazopsine已被证明对肝脏阶段具有特异性活性，但对血液形式的疟疾寄生虫无活性。抗疟药物的这种独特特异性严重限制了选择对数量和持续时间有限的寄生虫阶段具有耐药性的压力，从而使研究人员能够设想将真正的因果预防纳入疟疾控制计划。
Background The global spread of multidrug-resistant malaria parasites has led to an urgent need for new chemotherapeutic agents. Drug discovery is primarily directed to the asexual blood stages, and few drugs that are effective against the obligatory liver stages, from which the pathogenic blood infection is initiated, have become available since primaquine was deployed in the 1950s.Methods and Findings Using bioassay-guided fractionation based on the parasite's hepatic stage, we have isolated a novel morphinan alkaloid, tazopsine, from a plant traditionally used against malaria in Madagascar. This compound and readily obtained semisynthetic derivatives were tested for inhibitory activity against liver stage development in vitro (P. falciparum and P. yoelii) and in vivo (P. yoelii). Tazopsine fully inhibited the development of P. yoelii (50% inhibitory concentration [IC50] 3.1 mu M, therapeutic index [TI] 14) and P. falciparum (IC50 4.2 mu M, TI 7) hepatic parasites in cultured primary hepatocytes, with inhibition being most pronounced during the early developmental stages. One derivative, N-cyclopentyl-tazopsine (NCP-tazopsine), with similar inhibitory activity was selected for its lower toxicity (IC50 3.3 mu M, TI 46, and IC50 42.4 mu M, TI 60, on P. yoelii and P. falciparum hepatic stages in vitro, respectively). Oral administration of NCP-tazopsine completely protected mice from a sporozoite challenge. Unlike the parent molecule, the derivative was uniquely active against Plasmodium hepatic stages.Conclusions A readily obtained semisynthetic derivative of a plant-derived compound, tazopsine, has been shown to be specifically active against the liver stage, but inactive against the blood forms of the malaria parasite. This unique specificity in an antimalarial drug severely restricts the pressure for the selection of drug resistance to a parasite stage limited both in numbers and duration, thus allowing researchers to envisage the incorporation of a true causal prophylactic in malaria control programs.